Our overall objective is to localize chromosomal loci (and ultimately genes) that predispose to osteoporosis by performing a genome wide search using state-of-the-art molecular and statistical genetic approaches in a unique family collection, the Amish Family Osteoporosis Study. The Old Order Amish are ideal for these studies since they are a closed founder population who are relatively genetically homogeneous, and have very large family sizes and well documented genealogies. Since February 1997, Dr. Shuldiner recruited and studied 368 Amish individuals from 30 families. This proposal brings together three strong research groups with complementary interests: Alan Shuldiner, M.D. and Elizabeth Streeten, M.D. at the University of Maryland, Braxton Mitchell, Ph.D. at the Southwest Foundation for Biomedical Research, and Daniel McBride, Ph.D. at Johns Hopkins University. First, we will expand the Amish Family Osteoporosis Study from 368 to 1,000 subjects (about 100 families) by recruiting and phenotypically characterizing additional Amish subjects. Second, we will perform genome-wide quantitative trait linkage (QTL) analyses of bone mineral density and related traits to locate chromosomal regions containing osteoporosis susceptibility genes utilizing 391 polymorphic short tandem repeat (STR) markers spaced at approximately 10 cM intervals. Genome-wide association analyses, using transmission disequilibrium tests and other tests of association will be performed, to evaluate whether specific alleles and/or haplotypes shared across families are associated with variation in bone density and related phenotypes. We will also determine whether previously described genetic variation in genes for the vitamin D receptor (VDR), collagen type I alpha 1 (COLAIA1), and the estrogen receptor, influence phenotypic variation in bone density, and measures of bone formation and bone resorption. Finally, we will type additional markers in chromosomal regions showing possible linkage and/or associations and will perform linkage and association analyses using this denser marker set in order to strengthen signals and improve localization of genes influencing bone density and related quantitative traits. Discovery of osteoporosis susceptibility genes will provide (i) critical insights into molecular mechanisms, (ii) new molecular targets for therapeutics, and (iii) blood tests for the early detection of susceptibility individuals so that preventative interventions can be instituted. These advances will impact substantially on the quality of life of millions of older Americans with osteoporosis.